Hypercholesterolemia is known to be one of the prime risk factors for atherosclerosis and coronary heart disease, the leading cause of death and disability in Western countries.
There are agents known, however, that are very active antihypercholesterolemic agents which function by limiting cholesterol biosynthesis via inhibiting the enzyme, HMG-CoA reductase. These agents include the natural fermentation products, such as mevastatin, lovastatin and pravastatin, and semisynthetic analogs, such as simvastatin.
MEVACOR.RTM., which contains lovastatin as the active agent, and ZOCOR.RTM., which contains simvastatin as the active agent, are now commercially available for use as antihypercholesterolemic drugs. The reduction of the effective dosage amount which is anticipated to diminish the incidence of adverse experiences associated which these drugs would be extremely beneficial in view of the lifetime regimen of treatment of hypercholesterolemia.
Antihypercholesterolemic agents are useful for the treatment of arteriosclerosis, atherosclerosis, hyperlipidemia, familial hypercholesterolemia and like diseases in humans. They may be administered orally or parenterally in the form of a capsule, a tablet, an injectable preparation or the like. It is usually desirable to use the oral route. Doses may be varied, depending on the age, severity of hypercholesterolemia, body weight and other conditions of human patients but daily dosage for adults is within a range of from about 2 mg to 2000 mg (preferably 10 to 100 mg) which may be given in two to four divided doses. Higher doses may be favorably employed as required.
Utilizing controlled or sustained release technologies, a single administration of the indicated daily dosage amount delivers the drug to the patient over an extended period of time (i.e. 6 to 24 hours) to yield an equivalent or improved therapeutic effect while lowering the peak drug plasma levels. The response is apparently effected by improved hepatic extraction of the absorbed drug as the liver is the site of action of these antihypercholesterolemic agents. An additional benefit of this approach is the potential reduction in side effects associated with circulating drug.
Controlled delivery devices for the sustained release of therapeutically active agents are well known in the art. Generally, these devices may be characterized as either diffusion controlled systems, osmotic dispensing devices, dissolution controlled matrices, or erodible/degradable matrices.
U.S. Pat. No. 3,538,214 discloses a diffusion controlled device in which a tablet core containing an active ingredient is surrounded by a water insoluble coating which contains a film modifying agent soluble in the external fluids in the gastrointestinal tract.
An example of an osmotic device is described in U.S. Pat. Nos. 3,845,770 and 3,916,899 which is a core composition of an active agent and an osmotically effective solute which is enclosed by an insoluble semipermeable wall having a release means. Numerous modifications to these types of delivery devices have been described in the art in an effort to improve their release characteristics. U.S. Pat. Nos. 4,256,108; 4,160,452; 4,200,098, 4,285,987, 4,327,725, and 4,612,008 disclose such improved delivery devices.
U.S. Pat. No. 4,851,228 and co-pending U.S. patent application Ser. No. 073,781, filed Jul. 15, 1987 disclose systems which comprise an inner core compartment of osmotically active composition surrounded by an enclosing controlled porosity wall material that is substantially permeable to both solute and external fluid. These systems are osmotic dispensing devices for a broad range of therapeutically active agents. Co-pending U.S. patent application Ser. No. 348,099, filed May 1, 1989 discloses such a delivery system which is controlled through the influence of a controlled release solubility modulator contained within the drug delivery device. U.S. Pat. No. 4,795,644 also discloses such a delivery system which is controlled through the influence of a water insoluble, non-diffusible charged resin entity contained within the drug delivery device.
U.S. Pat. No. 4,755,180 discloses a dosage form comprising a beneficial agent and a polymer coated osmotically effective solute for regulating the solubility of the beneficial agent.
Numerous examples of diffusion controlled and erodible/degradable devices are discussed in detail in Controlled Drug Delivery: Fundamentals and Applications, 2nd Edition, J. R. Robinson and V. H. L. Lee, Eds., Marcel Dekker, Inc., New York and Basel, 1987, and in Controlled Drug Delivery: Basic Concepts, Vols I and II, S. D. Brunk, Ed., CRC Press Inc, Boca Raton, Fla., 1983.